Project Summary We seek to understand how structural polymorphisms in amyloid aggregates are associated with Alzheimer's disease (AD) pathogenesis, whether they contribute to disease heterogeneity analogous to strain variation in prion diseases and whether endogenous human antibodies to these different structures may be useful therapeutics and biomarkers for disease subtypes. We have raised 28 monoclonal antibodies that recognize different epitopes and distinguish the structural polymorphisms, so we want to test the hypothesis that antibodies that recognize some structures may be more effective than others in protecting against AD and may be useful biomarkers for AD and its subtypes. These insights have the potential to provide a much finer and detailed view of amyloid pathology and the significance of different types of amyloid deposits and reveal specific therapeutic targets. Advances in our understanding of A? amyloid structure have shown that peptide can adopt multiple alternative amyloid structures or polymorphs raising the question of whether this polymorphism is meaningful for pathogenesis and a contributor to disease polymorphisms. So far, at least 6 different A? fibril structures have been determined by solid state NMR and different oligomeric structures have been distinguished based on spectroscopy. Moreover, different fibril structures have been found in human brain with different AD clinical histories suggesting that polymorphisms may be associated with disease subtypes. Consistent with the structural polymorphisms reported, we have found that conformation dependent monoclonal antibodies can distinguish 9 immunologically and morphologically distinct types of amyloid deposits in human and transgenic mouse brain. We will establish the time course of the temporal evolution of the 9 specific amyloid types in transgenic mouse and determine how the 9 different amyloid types are associated with AD and its subtypes. Aducanumab is a human monoclonal antibody that is the first disease modifying therapy to prevent or slow cognitive decline in Alzheimer disease. Aducanumab was isolated from normal human blood, indicating that disease modifying antibodies are expressed in humans. This is an important result because it suggests that there may be other antibodies or combinations of antibodies that confer a more effective neuroprotective activity in humans. Using a random sequence, phage display library, we cloned and sequenced more than 75,000 random 12 mer sequences that interact with our 28 monoclonals. We discovered that there are unique patterns of amino acid sequence recognized by each of the antibodies, indicating that we can use this signature of immunoreactivity to identify individual antibodies reactive with different amyloid polymorphs in human serum or plasma. The goal of this proposal is to use this microarray to search for antibodies protective for AD and endogenous antibodies that are biomarkers of disease and disease subtype.